Appearance of amyloid in the islets of Langerhans coincides with changes in hormone concentrations and precedes overt diabetes in Macaca nigra as in aging human beings. Between the time of the initial deterioration of islet secretory cells and the development of diabetes, alterations in hormones and metabolites can contribute to metabolic dysfunctions and secondary pathological complications. Research is aimed at understanding the entire sequence of events that lead eventually to abnormal glucose tolerance. At the earliest times, morphological alterations are apparent in secretory cells even before appearance of amyloid; hormonal secretion is concurrently impaired. Results from biopsies performed on monkeys of various metabolic states allow correlation of morphological changes with hormonal dysfunctions. Increasing amounts of islet amyloid correlate with increasing severity of overt diabetes. Immunoreactive glucagon (IRG) concentrations increase several-fold at the time of the initial hormonal changes and appearance of amyloid. The IRG is the pancreatic, alpha cell form. Relationships are being sought between IRG concentrations and the islet lesion. The immunoperoxidase technique will be used to quantify viable alpha, beta and D cells, and to relate secretory cell changes to the hormonal and morphological alterations. Macaca nigra provides a unique model. Islet morphological alterations and hormonal secretory changes precede amyloid appearance; this allows early identification of a developing lesion which culminates in diabetes and its secondary complications. A similar syndrome occurs in aging human beings.